PROJECT ABSTRACT/SUMMARY For adults suffering from from end-stage lung disease, lung transplantation aims to extend survival, relieve disability, and improve health-related quality of life (HRQL). An overhaul in organ allocation policy in 2005 prioritized lung transplant for sicker and older adults without impacting one-year survival ? the primary measure of transplant efficacy. This overhaul has come at substantial cost, however, including recent trends towards increased disability, poorer HRQL, and increased longer-term mortality. There is an urgent need to discriminate candidates likely to survive after surgery with improved disability and HRQL and to identify new informative pre- transplant factors to aid in candidacy decision-making. Recently, we found that frailty was prevalent and associated with disability. In contrast to other solid organ transplant populations, only one of two well-established measures of frailty predicted risk of waitlist death/delisting in lung transplant candidates. Additionally, our early data suggests that established measures of frailty may be confounded by lung disease, resulting in misclassification. We also showed that protein biomarkers representing putative pathways of frailty (i.e., systemic inflammation, aging, and cachexia) are important in lung transplant candidates. Whether the pathways causing frailty are universal across heterogeneous lung diseases or whether sub-phenotypes of frailty (so called ?endotypes?) with distinct pathobiology, outcome risks, and treatment responses exist are unknown. Herein, we propose a prospective cohort study in three large U.S. lung transplant centers to address three fundamental and new areas in which frailty may inform the field of lung transplantation. In 624 lung transplant candidates, we will assess existing frailty measures as well as performance, biomarker, and anthropomorphic measures (including sarcopenia) relevant in lung disease. Of these candidates, 480 will ultimately undergo transplantation in whom we will evaluate survival, disability, and HRQL one year after transplant. In Aim 1, we will use operational measures of frailty domains relevant in lung disease to design a novel frailty index for lung transplantation. We hypothesize that this index will better quantify frailty-attributable vulnerability to stressors than existing measures developed in community-dwelling older adult populations. In Aim 2, we will utilize latent class analysis (LCA) to identify endotypes of frailty. We hypothesize that LCA that considers clinical and biomarker measures of mechanisms driving frailty will identify distinct endotypes in lung disease. In Aim 3, we will develop a clinical prediction model to identify those at risk for disability, poor HRQL, and death after lung transplant. We hypothesize that a model that includes frailty will better predict survival with improved disability and HRQL than a model without. In sum, this proposal will yield a novel measure of frailty relevant for adults undergoing lung transplantation and, possibly, those with lung disease undergoing other major surgeries; will provide new knowledge into the pathobiology of frailty in lung disease; and, finally, by considering survival and patient-centered outcomes, will yield a prediction model that will immediately aid informed decision making in a way that is not presently possible.